Rivaroxaban for Treatment of Suspected or Confirmed Heparin-Induced Thrombocytopenia Study

Abstract Rivaroxaban is an ideal potential alternative for treatment of heparin-induced thrombocytopenia because it is administered orally by fixed dosing, requires no routine coagulation monitoring and has been proven effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT Study prospectively evaluated the efficacy and safety of patients with suspected or confirmed HIT who were treated with rivaroxaban [NCT01598168 - investigator sponsored study funded by Bayer] Methods: Canadian multicenter, single-arm, prospective cohort study of patients with confirmed or suspected HIT (4Ts score ≥4) treated with rivaroxaban 15 mg bid until the diagnosis was supported or refuted using the local HIT assay. Participants with HIT (positive local assay result) received rivaroxaban 15 mg bid until platelet recovery (or until Day 21 if the patient had acute thrombosis; HITT) then stepped down to rivaroxaban 20 mg daily until Day 30. Central testing with the serotonin-release assay (SRA) was performed (not in real-time at all centres). HIT positive was defined as a 4Ts score ≥4 plus serotonin release ≥50%. The primary outcome measure was the incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days. Secondary objectives included incidence of symptomatic thromboembolism while on treatment with rivaroxaban (combined cohort) and the following outcomes among SRA-positive participants while on treatment with rivaroxaban: incidence of venous and arterial thromboembolism, incidence of major bleeding, and time to platelet recovery. Sample size of 200 participants (10 to 30 with SRA-confirmed HIT) was based on feasibility and an anticipated thrombotic event rate in the study population (combined cohort) of 6.5% at 30 days (5% in HIT negative; 11% in HIT positive while on rivaroxaban). Results: 22 participants (12 HIT positive) were enrolled between January 2013 and July 2015. The study was terminated early due to poor recruitment, but after enrolling the minimum expected number of HIT positive participants. Of the 12 HIT positive participants (SRA, mean release 95%), 3(25%) had HITT at time of study entry and 6 had received at least one dose of fondaparinux prior to study enrolment. Half of the HIT positive participants were enrolled in study after the SRA result had already been reported as positive. After 371 days of exposure to rivaroxaban (combined cohort), 1 HIT positive participant had possible symptomatic recurrent VTE (4.5%, 95% CI: 0 to 23.5%), 1 HIT positive participant had major bleeding (9 days after rivaroxaban was held) and there were 4 deaths (cancer 2, sepsis 1, end-stage COPD 1). The single episode of possible recurrent VTE was extension of previously documented apheresis catheter-related arm DVT in a HIT positive participant who presented on Day 7 with worsening arm pain. A repeat ultrasound showed extension of DVT; however a baseline scan had not been performed at time of study entry. Interestingly, the same participant failed treatment with fondaparinux prior to study enrolment (development of erythematous plaques at injection sites and failure of platelets to rise). His apheresis catheter was removed on Day 8, rivaroxaban was continued and complete resolution of his symptoms as well as platelet recovery was achieved. One HIT positive participant presented with evidence of bilateral lower limb arterial ischemia (HIT-related acute arterial thrombosis on documented chronic peripheral vascular disease) at the time of study enrolment. Despite achieving platelet recovery, he underwent bilateral below knee amputation on Day 16. Out of the 12 HIT positive participants, 11 achieved platelet recovery with mean time to recovery 9 days. The single participant who did not achieve platelet recovery received only 2 doses of rivaroxaban before it was held due to a transient rise in liver enzymes. Rivaroxaban was never restarted because he bled while receiving fondaparinux as an alternative. Conclusions: Rivaroxaban appears to be effective for treating patients with confirmed HIT, although lack of a comparator and a small sample size are limitations of our findings. The advantages of rivaroxaban over other agents currently used to treat HIT such as ease of administration, lack of routine coagulation monitoring and low cost make it an attractive option. Disclosures Linkins: Pfizer: Honoraria; Bayer: Honoraria, Research Funding. Off Label Use: rivaroxaban has not been approved for treatment of heparin-induced thrombocytopenia. Warkentin:W.L. Gore: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Honoraria; Pfizer: Consultancy. Pai:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Shivakumar:Bayer: Honoraria. Wells:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Research Funding. Wu:Pfizer Canada: Membership on an entity's Board of Directors or advisory committees; Leopharma: Membership on an entity's Board of Directors or advisory committees.

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Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant

Blood ◽

10.1182/blood-2018-120770 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. LBA-5-LBA-5 ◽

Cited By ~ 2

Author(s):

James Douketis ◽

Alex C. Spyropoulos ◽

Joanne M Duncan ◽

Marc Carrier ◽

Gregoire Le Gal ◽

...

Keyword(s):

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Perioperative Management ◽

Elective Surgery ◽

Bleeding Risk ◽

Advisory Board ◽

Advisory Committees ◽

Arterial Thromboembolism ◽

High Bleeding Risk

Abstract Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure. Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl<50 mL/min (Figure 1). A blood sample was obtained just before the procedure to measure residual DOAC levels (Appendix 2). Heparin bridging and preoperative coagulation testing were not used to manage patients. Patient follow-up occurred weekly for 30 days post-procedure for the primary clinical outcomes of major bleeding and arterial thromboembolism (Appendix 3). The incidence (95% confidence interval [CI]) of clinical outcomes was determined for each DOAC cohort using an intention-to-treat (ITT) analysis (interrupted at least 1 DOAC dose) and per-protocol analysis (adhering to DOAC interruption and resumption protocol). Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level <50 ng/ml occurred in 90.5% of patients in the apixaban cohort, in 95.1% of the dabigatran cohort and in 96.8% of the rivaroxaban cohort. Of 1007 patients having a high bleeding risk procedure, 832 (82.6%) had DOAC levels measured: 98.8% had a level <50 ng/mL (Table 4). Rates of major bleeding and arterial thromboembolism in the per protocol analysis were comparable to those of the ITT analysis (Table 5). Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (<2%) and ATE (<1%). Further, a high proportion of patients (>90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care. Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays). Acknowledgments: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap. Disclosures Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos:Janssen Scientific Affairs, LLC: Consultancy. Carrier:Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme:Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar:Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross:Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier:BMS-pfizer: Honoraria. Wu:Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold:Bristol Myers Squibb: Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Caprini:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer:Octapharma: Honoraria. Schulman:Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.

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A Randomized Study of Low Dose Oral Clofarabine 10 Mg Versus 20 Mg (flat dose) Daily × 5 for Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v120.21.3851.3851 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3851-3851

Author(s):

Stefan Faderl ◽

Guillermo Garcia-Manero ◽

Farhad Ravandi ◽

Jorge E. Cortes ◽

Zeev Estrov ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Randomized Study ◽

Patient Characteristics ◽

Median Number ◽

Infectious Complications ◽

Advisory Committees ◽

Platelet Recovery ◽

Flat Dose ◽

Secondary Mds

Abstract Abstract 3851 Clofarabine (CLO) is a nucleoside analog with activity in myeloid malignancies. We have previously reported an overall response rate (ORR) of 43% (CR rate 25%) in patients (pts) with higher-risk MDS treated with oral CLO at doses between 20 mg/m2 and 40 mg/m2 daily × 5 (S Faderl et al. J Clin Oncol 2010, 28: 2755). However, myelosuppression and infectious complications were frequent. We therefore developed a trial based on a Bayesian randomization design of CLO 10 mg vs 20 mg (flat dose) orally daily × 5 days with the objective to maintain reasonable efficacy and minimize toxicities. Cycles were repeated every 4 to 8 weeks for up to a total of 12. Pts were eligible if they had MDS with ≥ 5% blasts (including RAEB-t by FAB) or IPSS intermediate-2 and high-risk, and CMML. Hematopoietic growth factor support prior to and during the study was permitted. Thirty-two pts (19 RAEB [59%], 7 RAEB-t [22%], 2 MDS/MPN [6%], 4 CMML [13%]) were randomized. Patient characteristics were similar between the groups and are summarized in Table 1. Table 1: Patient Characteristics Characteristic 10 mg 20 mg N 16 16 Median age, yrs (range) 67.5 (43–87) 72.5 (54–84) Median WBC, ×109/L (range) 4 (1.2–121.3) 4.8 (0.4–47) Median blood blasts, % (range) 0.5 (0–25) 3.5 (0–32) Median marrow blasts, % (range) 12 (4–28) 12 (2–24) Secondary MDS, N (%) 9 (56) 4 (25) Median N prior therapies (range) 1 (0–3) 1 (0–4) Prior hypomethylator therapy, N 14 (88%) 13 (81%) Cytogenetics 5 (31) 6 (38) Diploid, N (%) 4 (25) 4 (25) -5/5q- and/or -7/7q- 4 (25) 2 (13) IM/not done Seven pts (22%) responded: 3 CR and 4 CR without platelet recovery (CRp). Four pts (25%) in the 10 mg group and 3 pts (19%) in the 20 mg group responded (differences not significant). Median remission duration was 6.5 months for all pts (6.5 months [10 mg]; 4.4 months [20 mg], p=.942). The median number of cycles was 2 in each treatment group with a range of 1–4 (10 mg) and 1–12 treatment cycles (20 mg), respectively. One pt in each group died. Median survival for the whole group was 8.5 months (8.2 months [10 mg]; 8.5 months [20 mg], p=.9). Clofarabine at both 10 mg and 20 mg orally daily × 5 has a comparable CR/CRp rate as do higher doses. Myelosuppression does still occur but prolonged myelosuppression has been rare. Even lower doses including at different schedules may still warrant further study. Disclosures: Faderl: Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine in MDS. O'Brien:Avila: Research Funding; Bayer: Consultancy; Bristol-Myers Squibb: Research Funding; Gilead Sciences: Consultancy, Research Funding; Celgene: Consultancy; Cephalon: Consultancy; CII Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Research Funding; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Seattle Genetics, Inc.: Consultancy; Sigma Tau Pharmaceuticals: Consultancy; Talon: Research Funding; The Medal Group: Speakers Bureau. Kantarjian:Genzyme: Research Funding.

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Two Years Versus Six Months of Oral Anticoagulation after a First Episode of Unprovoked Pulmonary Embolism: The Padis PE Multicenter, Double-Blind, Randomized Trial

Blood ◽

10.1182/blood.v124.21.lba-3.lba-3 ◽

2014 ◽

Vol 124 (21) ◽

pp. LBA-3-LBA-3

Author(s):

Francis Couturaud ◽

Olivier Sanchez ◽

Gilles Pernod ◽

Patrick Mismetti ◽

Patrick Jego ◽

...

Keyword(s):

Pulmonary Embolism ◽

Placebo Group ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Composite Outcome ◽

Advisory Committees ◽

Entire Study ◽

Warfarin Group ◽

Recurrent Vte

Abstract Background: Patients with a first episode of unprovoked pulmonary embolism have a high risk of recurrent venous thromboembolism (VTE) after anticoagulation is discontinued. Prolongation of anticoagulant therapy beyond the initial period of 3 to 6 months is associated with a significant reduction of recurrent VTE, but an excess of bleeding events. In addition, most studies assessing prolonged treatment did not follow the patients after treatment had been stopped. Thus, the optimal duration of anticoagulation in patients with a first unprovoked pulmonary embolism remains uncertain. Method: In a multicenter, randomized, double-blind, controlled trial, we compared an additional 18 months of warfarin (target International Normalized Ratio, 2 to 3) with placebo in patients with a first episode of unprovoked pulmonary embolism that had been initially treated with a vitamin K antagonist for 6 uninterrupted months. In both groups, all patients were followed up for an additional median period of 2 years after treatment had been stopped. Primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Secondary outcomes included the composite outcome during the entire study period (i.e. 18 months plus a median follow-up of 2 years), deaths not caused by pulmonary embolism or major bleeding and the components of the composite outcome during the treatment period and during the entire study period. All outcomes were centrally adjudicated. Results: A total of 371 patients were included in the study and analyzed on an intention-to-treat basis. During the treatment period, the composite outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 patients (13.5%) in the placebo group (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.09-0.55; p=0.0004). Recurrent VTE occurred in 3 (1.7%) patients in the warfarin group and in 25 (13.5%) in the placebo group (HR, 0.11; 95%CI, 0.03-0.37); major bleeding occurred in 4 (2.2%) patients in the warfarin group and in 1 (0.5%) in the placebo group (HR, 4.07; 95%CI, 0.45-36.38). Two deaths not related to the study outcome occurred in each group. During the entire median study period of 41 months, the composite outcome occurred in 33 (20.8%) patients in the warfarin group and in 41 (23.5%) in the placebo group (HR, 0.76; 95%CI, 0.48-1.20; p=0.24) (Figure 1). Recurrent VTE occurred in 28 (17.9%) patients in the warfarin group and in 39 (22.1%) in the placebo group (HR, 0.67; 95%CI, 0.41-1.08); major bleeding occurred in 6 (3.5%) patients in the warfarin group and in 4 (2.5%) in the placebo group (HR, 1.57; 95%CI, 0.44-5.55). Thirteen (11.9%) patients died in the warfarin group, four deaths being related to recurrent VTE and one to major bleeding; six (3.6%) patients died in the placebo group from a cause unrelated to recurrent VTE or bleeding (p=0.08). Of the 67 episodes of recurrent VTE, 52 (77.6%) were pulmonary embolism and 58 (86.6%) were unprovoked. Conclusion: After 6 months of anticoagulation for a first episode of unprovoked pulmonary embolism, extending anticoagulation for an additional 18 months was associated with a major reduction in the risk of recurrent VTE or major bleeding during the treatment period. However, this benefit was not maintained after discontinuation of anticoagulation. (ClinicalTrials.gov number NCT00740883). Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Disclosures Couturaud: Astra Zeneka: Co-investigator in clinical trial, Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees; Bayer: Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees. Sanchez:Bayer: Membership on an entity's Board of Directors or advisory committees. Mismetti:Bayer: Membership on an entity's Board of Directors or advisory committees; pfizer: Membership on an entity's Board of Directors or advisory committees; boerhinger ingelheim: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Jego:Bayer: Membership on an entity's Board of Directors or advisory committees; actelion: Research Funding; GlaxoSmithKline: Research Funding. Parent:Bayer: Membership on an entity's Board of Directors or advisory committees. Lorillon:Astra Zeneka: Membership on an entity's Board of Directors or advisory committees, symposium invitation Other; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Girard:Leo Pharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Lacut:Bayer-Healthcare: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Boehringer Ingelheim: Research Funding. Leroyer:Novartis: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Investigator in COPD clinical trials, Investigator in COPD clinical trials Other, Membership on an entity's Board of Directors or advisory committees; Astra Zeneka: Investigator in asthma clinical trials Other, Membership on an entity's Board of Directors or advisory committees. Decousus:Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Meyer:Sanofi-Aventis: Research Funding; LEO Pharma: Research Funding; Bayer: Research Funding; Boehringer Ingelheim: Research Funding. Mottier:Pfizer: Membership on an entity's Board of Directors or advisory committees; bayer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding.

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Major Bleeding Complications Among Patients Treated with Ibrutinib and Concomitant Antiplatelet, Anticoagulant, or Supplemental Therapy

Blood ◽

10.1182/blood.v128.22.4387.4387 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4387-4387 ◽

Cited By ~ 4

Author(s):

Aaron Pavlik ◽

Hallie Barr ◽

Emily Dotson ◽

John C. Byrd ◽

Kristie A. Blum ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Event ◽

Antiplatelet Agents ◽

Bleeding Complications ◽

Bleeding Events ◽

Advisory Committees ◽

Major Bleeding Events

Abstract Background: Ibrutinib, an orally bioavailable small molecular inhibitor of Bruton's tyrosine kinase (BTK), is an approved therapy for chronic lymphocytic leukemia (CLL), relapsed mantle cell lymphoma (MCL) and Waldenstrӧm's macroglobulinemia (WM). Beyond B lymphocytes, BTK signaling is important for collagen-mediated platelet activation, and BTK inhibition has been associated with primary hemostatic bleeding events (Levade et al Blood 2014). Although serious bleeding events have been uncommon (1-5%) in clinical trial populations, there is limited data describing the potential for increased serious bleeding incidence when ibrutinib is co-administered with other agents affecting the clotting cascade or platelet function. Methods: We conducted a retrospective cohort study to evaluate the incidence of major bleeding in patients receiving ibrutinib concomitantly with antiplatelet agents (non-steroidal anti-inflammatory agents, ADP inhibitors), anticoagulants (heparins, warfarin, novel oral anticoagulants), or supplements with potential anticoagulant activity (vitamin E and fish oil). Major bleeding events were identified using criteria developed by the International Society on Thrombosis and Haemostasis (Schulman et al J Thromb Haemost 2005). Patients 18-89 years of age and treated with ibrutinib for CLL, MCL, or WM between March 1, 2010 and March 1, 2015 were included. The primary endpoint of this study was the incidence of major bleeding events, but we also sought to identify risk factors associated with the development of major bleeding, focusing on potential drug interactions. Based on the historic prevalence of major bleeding in ibrutinib clinical studies, we calculated that at least 20 major bleeding events would need to be identified in order to perform blinded multinomial regression on the collected data of an estimated 400 patients. Results: 437 eligible patients were included in the analysis. Patients were overwhelmingly male (71.4%) and white (94.8%), with a mean age of 67.1 years (range: 29-89). 53.1% received ibrutinib as participants of a clinical trial, and the remainder received standard-of-care ibrutinib treatment. The table (upper panel) summarizes use of concomitant antihemostatic agents by presence or absence of major bleeding events. Characteristics of the major bleeding events are further detailed in the lower panel. The most commonly observed concomitant antihemostatic medication was aspirin, with 147 patients (33.6%) being exposed to aspirin within the study period. Fourteen instances of major bleeding were observed, corresponding to an overall incidence of 3.2%. These major bleeding events all occurred in CLL patients receiving ibrutinib at the standard dose of 420 mg daily. Two patients had platelet counts less than 50 k/µL at time of the bleeding event. One-half of the major bleeding events were observed in the absence of an antihemostatic medication, and 2 of the observed major bleeding events resulted in death (1 received concomitant warfarin). Fourteen patients (3.3%) in the group without major bleeding were on anticoagulation, 4 being warfarin. The most common sites of major bleeding were gastrointestinal (50%), intracranial (14.3%) and thoracic (14.3%). While most patients developing major bleeding permanently discontinued ibrutinib (57.1%), approximately one third of the patients who developed major bleeding subsequently resumed ibrutinib following resolution of the bleeding event. Subsequently, these patients did not experience a recurrent major bleeding event. The rate of major bleeding did not meet power to detect statistical differences in bleeding events when comparing concomitant therapy, Conclusions: Our observed incidence of major bleeding is consistent with previous controlled clinical trials, suggesting similar safety profile when ibrutinib is used outside of a controlled setting. Major bleeding events were uncommon despite the frequent co-administration of antiplatelet agents. However, because we modified practice early to avoid therapeutic anticoagulation during ibrutinib therapy whenever possible, the number of patients receiving such drugs in combination was small and precludes inferences regarding safety. Table Table. Disclosures Blum: Pharmacyclics: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Woyach:Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding. Christian:Pharmacyclics: Research Funding; Janssen: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Efficacy and Safety of Primary Thromboprophylaxis for the Prevention of Venous Thromboembolism in Patients with Cancer and Central Venous Catheter: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2021-146904 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2139-2139

Author(s):

Allen Li ◽

Willem Brandt ◽

Cameron Brown ◽

Tzu-Fei Wang ◽

Rick Ikesaka ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Venous Catheter ◽

Bleeding Complications ◽

Efficacy And Safety ◽

Central Venous ◽

Advisory Committees ◽

Patients With Cancer

Abstract Background Venous thromboembolism (VTE) is a leading cause of mortality in patients with cancer and is associated with significant morbidity and healthcare expenditure. The risk of VTE is also increased following the insertion of a central venous catheter (CVC) for chemotherapy deliverance and supportive care. The risks and benefits of primary thromboprophylaxis in patients with cancer and newly inserted CVC are unclear. Objective We sought to assess the rates of VTE and major bleeding complications to determine the safety and efficacy of primary thromboprophylaxis in adult patients with cancer and a CVC. Methods A systematic search of MEDLINE, EMBASE, and all EBM was conducted. Randomized controlled trials (RCTs) of adult patients with cancer and a CVC receiving primary thromboprophylaxis or observation/placebo were included. The primary efficacy and safety outcomes were total VTE and major bleeding episodes, respectively. Results A total of 9 RCTs (3155 patients) were included in the analysis. The total rates of VTE were significantly lower in patients receiving primary thromboprophylaxis compared to those not receiving primary prevention (7.6% vs. 13%; Odds Ratio (OR) 0.51, 95% CI 0.32 to 0.82, p < 0.01, I² = 52%) (Figure 1). The rate of major bleeding complication was not increased in patients receiving thromboprophylaxis (0.9% vs. 0.7%; OR 1.12, 95% CI 0.29 to 4.40, p = 0.87, I² = 32%) (Figure 2). Conclusions Primary thromboprophylaxis significantly reduced the risk of VTE without increasing the risk of major bleeding complications in patients with cancer and CVC. Future studies are needed to confirm these findings. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Ikesaka: LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wells: Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; BMS/Pfizer: Research Funding; Servier: Honoraria. Carrier: Servier: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Blood ◽

10.1182/blood-2021-152183 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3376-3376

Author(s):

Olga Salamero ◽

Tim C.P Somervaille ◽

Antonieta Molero ◽

Evelyn Acuña-Cruz ◽

Jose Pérez-Simón ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Objective Response ◽

Therapeutic Options ◽

Dose Finding ◽

Open Label ◽

Advisory Committees ◽

Platelet Recovery

Abstract Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

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Pathologic Misdiagnosis in Children with Suspected Burkitt Lymphoma Associated with Early Mortality

Blood ◽

10.1182/blood-2018-99-116263 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2271-2271

Author(s):

Chloe Stiggelbout ◽

Megan Real-Hall ◽

Innocent Mutyaba ◽

Elizabeth M Krantz ◽

Scott Adams ◽

...

Keyword(s):

Sample Size ◽

Board Of Directors ◽

Burkitt Lymphoma ◽

Research Funding ◽

Early Mortality ◽

Disease Stage ◽

Advanced Stage ◽

Advisory Committees ◽

Kaplan Meier ◽

Stage Disease

Abstract INTRODUCTION Burkitt lymphoma (BL) is one of the most common childhood cancers across sub-Saharan Africa (Walusansa et. al, 2012). Unfortunately, the one-year survival rate of children with BL treated in low- and middle- income countries (LMICs) remains low, compared to higher-resource settings (Howard et al., 2008, Stanley et al., 2016, Buckle et al., 2016). Factors in LMICs contributing to this disparity include inability to give high-dose chemotherapy, lack of supportive care measures, and treatment abandonment (Gopal, 2018). The impact of diagnostic inaccuracies on BL outcome has not been well-studied to date. PURPOSE To determine the frequency and impact of an incorrect histopathologic diagnosis in children with suspected BL presenting to the Uganda Cancer Institute (UCI). METHODS Study Design and Participants -A sample of subjects with available tissue biopsies was selected from a cohort of children presenting to the UCI with suspected BL between July 2012 and July 2017. Laboratory Methods - Formalin fixed, paraffin embedded (FFPE) tumor blocks were obtained from local Ugandan pathology laboratories and sectioned in a single, central Ugandan histology lab. Slides were then shipped to a US-based reference laboratory for front-line evaluation by Hematoxylin and Eosin (H&E) staining, by intentionally streamlined immunohistochemistry (IHC) for CD20, c-Myc, and TdT detection, and by EBER-1 in situ hybridization (ISH) for EBV detection. A diagnosis of BL required the expected H&E appearance and prominent tumor expression of CD20, c-Myc, and EBER-1, with no significant TdT expression. For equivocal cases, additional CD10, CD21, bcl-2, and Ki67 IHC could be employed. Misdiagnosis Definition - A discrepancy between the pathologic diagnosis confirmed by IHC/ISH at the US-based laboratory, and the diagnosis that determined treatment in Uganda. Clinical and Statistical Analysis - Advanced disease stage included Ziegler stage C, D, or AR based on physical exam. Kaplan-Meier and Cox regression analysis were applied to evaluate survival. RESULTS We enrolled 97 participants of with a median age of 7 (interquartile range (IQR) 4-10); 69% were male, 47% had ECOG status 0-1, and 48% had advanced stage disease (though 22% had missing staging information - Table 1). The majority of patients had facial involvement, while less than half of the evaluable patients had abdominal involvement. Twenty percent of biopsies (19/97) were misdiagnosed. Median follow-up time was 7.1 (IQR 1-12) months, during which 68% (13/19) of misdiagnosed patients died, compared to 49% (38/78) of correctly diagnosed patients. The Kaplan Meier estimate of survival among the entire cohort was 42% (95%CI 31-52%); those with and without a misdiagnosis had survivals of 20% (95% CI 5-42%) and 46% (95% CI 34-57%), respectively (Figure 1). The logrank value comparing survival among those with and without a misdiagnosis was 0.0047. CONCLUSIONS BL diagnosis remains challenging in resource-limited areas, with a high misdiagnosis rate of 20% in this cohort. Misdiagnosed patients tended to be younger and to have more advanced stage disease. We observed a significant positive association between misdiagnosis and early mortality. Misdiagnosis likely contributes to poorer BL survival in low-resource settings by increasing the chance of treatment for the wrong tumor type. SIGNIFICANCE Study limitations include relatively small sample size and the potential for selection bias among patients who had tissues samples available; however, the 12-month survival of all patients diagnosed with BL at the UCI during the study period was around 55%, and not markedly different from the 42% seen here. Next steps include a repeat study with a larger sample size. Finally, our novel IHC/ISH diagnostic algorithm, requiring 6 total slides (including 1 control slide to assess RNA quality), worked with high sensitivity and specificity, and will be described separately. Disclosures Real-Hall: Phenopath Laboratories: Employment. Adams:Burkitt Lymphoma Fund for Africa: Membership on an entity's Board of Directors or advisory committees, Research Funding. Uldrick:Celgene: Research Funding; Celgene: Patents & Royalties: 10,001,483 B2; Merck: Research Funding. Casper:Janssen: Consultancy, Research Funding; Up to Date: Patents & Royalties; TempTime: Consultancy, Other: Travel, Accommodation, Expenses; GSK: Other: Travel, Accommodation, Expenses; Roche: Consultancy, Other: Travel, Accommodation, Expenses. McGoldrick:Burkitt Lymphoma Fund for Africa: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Employment. Kussick:Phenopath Laboratories: Employment, Equity Ownership.

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Next-Generation Sequencing to Assess the Impact of Low Dose Melphalan on Residual Disease before High-Dose Melphalan and Stem Cell Transplant in Multiple Myeloma

Blood ◽

10.1182/blood-2021-148220 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4933-4933

Author(s):

Ehsan Malek ◽

Mary Hislop ◽

Leland Metheny ◽

Molly Gallogly ◽

Marcos J.G. de Lima ◽

...

Keyword(s):

Sample Size ◽

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Residual Disease ◽

Tumor Burden ◽

High Dose ◽

Cell Transplant ◽

Size Estimation ◽

Advisory Committees

Abstract High-Dose Melphalan (HDM) followed by stem cell transplant (SCT) remains the standard-of-care for transplant-eligible patients newly-diagnosed with multiple myeloma (MM). However, ~1/3 of patients relapse <2 years after undergoing HDM-SCT, indicating that melphalan-sensitivity is limited to a subset of patients and is currently not predictable. Currently, models that predict melphalan-resistance before proceeding to transplant are lacking. Rather, transplant-eligibility is defined mostly based on adequate organ function and performance status. Therefore, there is an urgent and unmet clinical need to develop strategies that accurately predict melphalan sensitivity among MM patients prior to HDM-SCT and save melphalan-resistant patients from undergoing this highly morbid procedure, if no demonstrable benefit is expected from it. Traditional disease-measurement methods based on International Myeloma Working Group (IMWG) criteria rely on the secretory function of myeloma cells and measure monoclonal protein levels. Following induction therapy, pre-transplant monoclonal protein levels are usually very low, and further reduction in myeloma secretory function are not detectable. In addition, the long half-life of monoclonal proteins makes assessing short-term disease changes problematic. Methods to accurately detect minor changes in disease burden following a low dose of melphalan (LDM) as a marker of melphalan sensitivity are needed to better predict patient responses to LDM. Next-generation sequencing (NGS), is an alternative approach that may allow for the highly sensitive, rapid, real-time detection of minuscule changes in tumor volume that are not influenced by the long half-life of monoclonal proteins. Here, we propose to use NGS-based tumor assessment to evaluate changes in disease volume following LDM before proceeding to HDM-SCT. Evidence is lacking to determine whether a single LDM generates a decrease in myeloma burden that is measurable by NGS. Our central hypothesis is that NGS of bone marrow aspirates from newly-diagnosed, post-induction transplant-eligible MM patients will provide a method to precisely determine the effect of LDM on disease burden. ClonoSEQ assay is an FDA-cleared, highly sensitive, specific, and standardized method to detect and monitor MRD, in MM patients. clonoSEQ leverages the power of NGS and offers an accurate and reliable way to assess how disease burden changes over time in response to treatment. Therefore, we propose a proof-of-principle study to assess the validity of this strategy and to provide essential data for future trial design investigating individualized approaches based on NGS sequencing and low doses of therapeutic agents. We will test the central hypothesis that LDM, administered at 16 mg/m 2, generates a detectable reduction in tumor burden measured by NGS. A detectable reduction in tumor burden is defined as a ≥ 20% decrease in NGS clonal count in at least 30% of subjects. We will administer propylene glycol-free melphalan formulation (EVOMELA) due to greater stability upon reconstitution than AlKERAN formulation in order to diminish the variability in the effective administered dose. The primary and secondary objectives and endpoints of the study are listed in Table-1,2. Statistical Considerations: Clonoseq detects measurable residual disease at the level of a single cell given sufficient sample input. The specific hypothesis of this pilot trial is LDM produces a measurable disease reduction that is readily detectable by clonoSEQ with at least a 20% reduction in at least 30% of patients. Assuming a 100% yield for VJD clonal sequencing and calibration efficacy by clonoSEQ, the sample size required to test the null hypothesis of 5% patients with positive MRD test against alternative 30% patients with positive MRD test is 16 patients. The sample size estimation is using two-sided chi-square test with 80% power. The sample size estimation is n = 21, when power = 90% based on one sample Binomial distribution theory. We will assume 20% failure rate for VJD clonal sequencing and calibration efficacy by clonoSEQ. Therefore, by enrolling 20 patients, we expect that at least 16 patients will have MRD assessable by NGS method. Figure 1 Figure 1. Disclosures Malek: BMS: Honoraria, Research Funding; Amgen: Honoraria; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board; Cumberland Inc.: Research Funding; Takeda: Honoraria; Janssen: Other: Advisory board ; Medpacto Inc.: Research Funding. Metheny: Incyte: Speakers Bureau; Pharmacosmos: Honoraria. de Lima: Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

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Effect of Romiplostim on Health-Related Quality of Life in Children with Immune Thrombocytopenia and Associated Burden in Their Parents: Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽

10.1182/blood.v126.23.37.37 ◽

2015 ◽

Vol 126 (23) ◽

pp. 37-37 ◽

Cited By ~ 2

Author(s):

Susan D Mathias ◽

Xiaoyan Li ◽

Melissa Eisen ◽

Nancy Carpenter ◽

Ross D Crosby ◽

...

Keyword(s):

Sample Size ◽

Board Of Directors ◽

Research Funding ◽

Stock Ownership ◽

Platelet Response ◽

Phase 3 ◽

Advisory Committees ◽

Parental Burden ◽

Response Status ◽

Parent Proxy

Abstract Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count levels and increased risk of bleeding. Symptomatic ITP in children can have a negative impact on their health-related quality of life (HRQoL) and increase their parents' burden. The effect of romiplostim (a thrombopoietin receptor agonist) on HRQoL and parental burden was evaluated in a phase 3 study of children with ITP. Methods: In a phase 3, randomized, double-blind, placebo-controlled study on efficacy and safety of romiplostim, children (<18 years) with ITP ≥ 6 months were randomized to weekly romiplostim or placebo for 24 weeks. The Kids' ITP Tool (KIT), a psychometrically-valid disease-specific HRQoL instrument (Klaassen Ped Blood Cancer2007), was administered to children and/or their parents at baseline, weeks 8, 16, and 25. All three KIT versions were used: Child self-report (to assess HRQoL of children ≥7 years), Parent/Proxy (to assess HRQoL of children <7 years via parent proxy), and Parent self-report (to assess impact of children's ITP on parental burden, for children of all ages). Each KIT version contains 26 items, summarized in a single score ranging from 0 to 100. Higher Child or Parent/Proxy KIT scores reflect better HRQoL of a child with ITP, and higher Parent KIT scores reflect less parental burden. Among efficacy endpoints of the study, overall platelet response was defined as achieving a weekly platelet response (platelet count ≥ 50 x 109/L) for ≥ 4 weeks during weeks 2 to 25, and durable platelet response was defined as achieving a weekly platelet response for ≥ 6 weeks during weeks 18 through 25. As exploratory endpoints of the study, changes in KIT scores from baseline to each follow-up assessment were estimated separately by treatment group (romiplostim or placebo) and by overall/durable platelet response status (yes/no). A mixed effects repeated measures analysis was conducted to estimate the difference in changes of Child and Parent KIT scores between romiplostim group and placebo group, controlling for baseline score, child's age, child's gender, and child's race (analysis of Parent/Proxy data was not conducted due to small sample size). Results: Sixty-two patients were enrolled and randomized to receive romiplostim (42 patients) and placebo (20 patients). Mean age was 9.6 years (range: 3-17, 16 patients <7 years), 57% were female, and 66% were white. Overall and durable platelet response was achieved by 34 and 24 patients, respectively. In general, changes in KIT scores by treatment group and overall platelet response status showed numerically greater and more often statistically significant improvements from baseline to each assessment for children receiving romiplostim (vs placebo) and for platelet responders (vs non-responders) (see Tables 1 and 2). Results based on durable response status were similar to those based on overall response status (data not shown). In the mixed effects analysis, greater improvement from baseline to week 8/16/25 on Parent KIT score was found in the romiplostim group vs placebo (by approximately 8 points, p-value<0.05); no significant difference was found between groups for Child KIT score. Conclusion: Romiplostim treatment is associated with reduced parental burden (measured by Parent KIT score). In some instances sample sizes were small for other KIT versions; therefore, results should be interpreted with caution. Table 1. Mean Change from Baseline in KIT Scores by Treatment Arm KIT Version Assessment week (sample size for romiplostim, placebo) Romiplostim Mean (95% CI) PlaceboMean (95% CI) Child 8 (n=28,11) 16 (n=27,10) 25 (n=28,11) 9 (4, 15) 11 (5, 16) 14 (7, 20) 9 (1, 18) 8 (-3, 20) 10 (-1, 20) Parent/Proxy 8 (n=8,2) 16 (n=8,3) 25 (n=9,3) -0.9 (-7, 5) -0.4 (-12, 11) 8 (2, 13) -40 (-108, 23) -1 (-86, 84) -10 (-80, 59) Parent 8 (n=40,16) 16 (n=39,17) 25 (n=37,16) 13 (10, 17) 15 (10, 21) 18 (12, 23) 4 (-6, 13) 12 (4, 20) 13 (4, 22) Table 2. Mean Change from Baseline in KIT Scores by Overall Platelet Response KIT Version Assessment week (sample size for responders, non-responders) Responders Mean (95% CI) Non RespondersMean (95% CI) Child 8 (n=23,17) 16 (n=22,16) 25 (n=23,16) 11 (4, 18) 11 (4, 18) 16 (8, 24) 4 (-5, 12) 8 (1, 15) 8 (1, 15) Parent/Proxy 8 (n=7,5) 16 (n=8,5) 25 (n=8,6) 0.9 (-7, 9) 4 (-10, 18) 9 (1, 17) -15 (-44, 13) -4 (-31, 22) -3 (-23, 17) Parent 8 (n=30,26) 16 (n=30,26) 25 (n=29,24) 11 (7, 14) 14 (7, 20) 17 (10, 24) 10 (3, 18) 15 (9, 21) 15 (9, 21) Disclosures Mathias: Amgen: Research Funding. Li:Amgen: Employment, Other: Stock Ownership. Eisen:Amgen Inc: Employment, Other: stock ownership. Carpenter:Amgen: Employment, Other: Stock Ownership. Crosby:Amgen: Research Funding. Blanchette:Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Other: Data Safety Monitoring Board; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Predicting Response to Hypomethylating Agents in Patients with Myelodysplastic Syndromes (MDS) Using Artificial Intelligence (AI)

Blood ◽

10.1182/blood-2019-126275 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2089-2089

Author(s):

Nathan Radakovich ◽

Mikkael A. Sekeres ◽

Cameron Beau Hilton ◽

Sudipto Mukherjee ◽

Jacob Shreve ◽

...

Keyword(s):

Neural Network ◽

Sample Size ◽

Board Of Directors ◽

Research Funding ◽

Validation Cohort ◽

Data Monitoring Committee ◽

Small Sample ◽

Patient Specific ◽

Hypomethylating Agents ◽

Advisory Committees

Introduction While the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) improve cytopenias and prolong survival in MDS patients (pts), response is not guaranteed. Timely identification of non-responders could prevent prolonged exposure to ineffective therapy, thereby reducing toxicities and costs. Currently no widely accepted clinical or genomic models exist to predict response or resistance to HMAs. We developed a clinical model to predict response or resistance to HMA after 90 days of initiating therapy based on changes in blood counts using time series analysis technology similar to the kind used in Apple's Siri or Google Assistant. In the setting of voice recognition, the sequence and context of words determines the meaning of a sentence; similarly, we hypothesized that the pattern of changes in MDS pts' blood counts would predict response or resistance early during treatment. Methods We screened a cohort of 107 pts with MDS (per 2016 WHO criteria) who received HMAs at our institution between February 2005 and July 2013 and had regular CBCs drawn during treatment. Mutations from a panel of 60 genes commonly mutated in myeloid malignancy were included. Responses were assessed after 6 months of therapy per International Working Group (IWG) 2006 criteria. Pts were divided randomly into training (80%) and validation (20%) cohorts. To address the potential for bias due to a small sample size, an oversampling algorithm was used to cluster similar pts based on their CBC data, Revised International Prognostic Scoring System (IPSS-R) score, and % bone marrow blasts at the time of diagnosis. CBC data from the first 90 days of treatment were fed into deep neural network (recurrent neural network) and decision tree algorithms, which were trained to predict whether pts would achieve a response (defined as complete remission (CR), partial remission (PR), or hematologic Improvement (HI)). Area under the curve (AUC) was used to assess model performance. Important features that impact the algorithm's predictions were extracted and plotted. Results 20747 unique data points were used, including CBC, clinical and genomic data. Among 107 pts, 61 (57.0%) received AZA only, 19 (17.8%) DAC only, 4 (3.7%) received both DAC and AZA, and 23 (21.5%) received HMA with an additional agent. Median age was 69 years (range: 37-100 years), and 27 (26.4%) were female. Forty pts (37.4%) were very low/low risk, 32 (29.9%) intermediate, 19 (17.8%) high, and 16 (14.9%) very high risk per IPSS-R. Responses included 23 (22.5%) CR, 2 (1.9%) marrow CR, 4 (3.9%) PR, and 20 (19.6%) HI. The most commonly mutated genes were ASXL1 (17.6%), TET2 (16.7%), SRSF2 (15.7%), SF3B1 (11.8%), RUNX1 (10.8%), STAG2(10.8%), and DNMT3A (10.8%). The median number of mutations per sample was 1 (range, 0-11), and 40 pts (39.2%) had > 3 mutations per sample. When trained using absolute values and changes in CBC values, the model's AUC was 0.95 in the training cohort and 0.83 in the validation cohort. When the cohort was oversampled to 1000 pts, the validation cohort AUC increased to 0.89. Feature extraction algorithms identified increases in MCV and RDW during weeks 2-8 of treatment, increased proportion of lymphocytes, decreased proportion of monocytes, and increased platelet counts during weeks 6-8 as factors favoring response to HMA. The model provides personalized, patient-specific predictions that correlate with blood counts (Figure 1). Conclusions We describe a machine learning model that monitors changes in blood counts during therapy with HMA to predict response or resistance to HMA in MDS pts. Such a model can be used to develop novel trial designs wherein pts predicted to not respond after 90 days of HMA treatment could be assigned to an investigational agent. Conversely, it would help inform the decision to continue HMA therapy in pts predicted to respond. Increasing sample size with oversampling dramatically increased model accuracy; a larger cohort of pts treated at different institutions is currently under development. Disclosures Sekeres: Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Nazha:Novartis: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee.

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